6-fluoro androstanes



United States Patent 3,016,387 G-FLUORO ANDROSTANES John C. Babcock and .3 Allan Campbell, Kalamazoo Township, Kalamazoo County, Milton E. Herr, Kalamazoo, John A. H022, Kalamazoo Township. Kalamazoo County, and Raymond L. Pcderson, Charleston Township, Kalamazoo County, Mich, assignors to The Upiohn Company, Kalamazoo, Mich, a corporation of Delaware I NoDrawing. Filed Sept. 28, 1959,,SenNo. 842,573 I 14 Claims. (Cl. 260-3973) This invention relates to novel 60cand 6,8-luoro steroids and is more particularly concerned with 6-fluoro-17a alkyl-17B-hydroxyandrostan-3-ones and the 17-acylates thereof, 6-fiu-oro-17a-alkyl-17fl-hydroxy-19 norandrostan- 3-ones and the 17-acylates thereof, 6-fluoro-17a-alkyl- 3,17B-dihydroxyandrostanes and the 17-acylates thereof,

acylates thereof, 6-fluoro-3-hydroxyandrostan-17-ones, 6-

fluoro 3-hydroxy-l9-norandrostan-17-ones, 6-fiuoro-3-hydroxyandrostane-l1,17-diones, 6-flnoro-3 hydroxy 19- norandrostane-l1,17-diones, 6-fiuoro 3,1173 dihydroxyandrostan-17-ones, and 6-fiuo-ro 3,1113 dihydroxy 19- norandrostan-17-ones, represented by Formula 113 below, and intermediates and methods used in the preparation thereof.

In this application the wavy line appearing at the 6-position, in the formulae below, is a generic expression including the alpha (a) and beta (5) configuration. Furthermore, when the term androstan or androstane is not preceded by the symbol 511 or 5,6it is meant to be a generic term inclusive of the 5:1 and 5B configuration.

Some of the novel compounds of this invention are represented by the formula:

1. til a Patented Jan. 9, 1962 the'group consisting of the carbonyl radical C:O) and the hydroxymethylene radical CHOH).

- The compounds of Formula IA possess useful therapeutic properties. They possess the ability to modify the secretion of gonadot-ropins and in addition exhibit androgenie,anabolic, anti-osteoporotic, and central nervous systern regulating activity. They are thus'useful in the treatment of; debilitated, osteoporotic and hypo-gonadal conditions. 7

Administration of the'steroidsof Formula-IA can be in conventional dosage forms such as pills, tablets, capsules, syrup-s, or elixirs for oraluse, or in liquid forms which are adaptable to the natural and synthetic steroid hormones for injeotable products. v

The novel compounds of Formula IA can be prepared in accordance with the following reaction scheme:

A CH3 CHz III A I I no H E F Iva wherein R, R and R have the same meaning as previously given.

The starting steroids for the preparation of the compounds of Formula IA are, for example, 6-fiuoro-17aalkyl-17fl-hydroxy-4-androsten-3-ones and the l7-acylates thereof and 6-fluoro-l7a-alkyl-l7fl hydroxy 19 nor 4- androsten-3-ones and the 17-acylates thereof, disclosed in copending application Serial No. 699,502, filed November 29, 1957, now US. Patent 2,838,500, granted June 10, 1958.

The process for the preparation of the compounds of Formula IA comprises catalytically hydrogenating compounds of the type represented by' Formula IIA, for example, 6-fl-uoro-17a-a1ky1-17B-hydroxy-4-androsten-3-ones and the 17-acylates thereof and 6-fluoro-17a-alkyl-17fi-hydroxy-l9-nor-4-androsten-3-ones and the 17 acylates thereof, to obtain the compounds of Formula IIIA, for example, 6-fluoro-17a-alkyl-l7fi-hydroxyandrostan-3-ones and the 17-acylates thereof and 6-fluoro-17m-alkyl-17 8- hydroxy-19-norandrostan 3 ones and the 17 acylates thereof, respectively.

The catalytic hydrogenation of the compounds of Formula HA to produce the compounds of Formula IIIA is accomplished by treating the compounds of Formula IIA with hydrogen in the presence of a noble metal catalyst, for example,.palladiurn, rhodium, and the like, preferably palladium. The noble metal catalyst can be supported on a carrier, for example, charcoal, alumina, zeolite zinc oxide, and the like. The reaction can be carried out at pressures of from atmospheric pressure to 100 pounds per square inch gauge, preferably at pressures between five and fifteen poundsper square inch gauge. The hydrogenation reaction is preferably carried out in the presence of a solvent, such as an organic solvent, for example, isopropyl alcohol, 95 percentethyl alcohol, tertiary butyl alcohol, acetone, methyl ethyl ketone, diox'ane, ethyl acetate, and the like, or an alcohol, for example, ethyl alcohol, containing ten percent by volume of a 5 N solution of an aqueous acid, for example, hydrochloric acid, hydrobromic acid, sulfuric acid and the like,

The thus-obtained compounds of Formula IIIA are then reduced with a metal hydride, for example, lithium aluminum hydride or a metal borohydride, preferably an alkali-metal borohydride, for example, sodium .borohydride, in a solvent which does not react readily with. the reducing agent, to produce the compounds of Formula IVA, for example, 6-fluoro 17a alkyl-3,17B-dihydroxyandrostanes and the 17-acylates thereof and 6-fluoro-17aalkyl-3,17fi-dihydroxy-19-norandrostanes and the 17-acylates thereof. When lithium aluminum hydride is used, the reaction is carried out in the presence of an ethertype solvent, for example, dioxane, ethyl ether, tetrahydrofuran, and the like. When an alkali-metal boroh'ydride is used, the reaction is carried out in the presence of an alcohol, for example, methanol, ethanol, isopropanol, and the like, or in the presence of pyridine, dimethylaniline, and the like.

6-fluoro-17a-alkyl-3,17,3-dihydroxyandrostanes and 6- fluoro-17 x-alkyl-3,17fl dihydroxy-19-norandrostanes can be acylated at the 3-position according to procedures well known in the art for the 3-acylation of dehydroepiandrosterone and 17a-methyl-5-androstene-3,8,17,8-diol to give 6-fluoro-17a-alkyl-3,17fi-dihydroxyandrostane 3- acylates and 6-fluoro-17e-alkyl-3,17B-dihydroxy-19-norandrostane 3-acylates, respectively. The 3-acylation of 6-fluoro 17a-alkyl-3,17fl-dihydroxyandrostane l'l-acylates and 6-fluoro-17a-alkyl-3,17,8-dihydroxy-19-norandrostane 17-a'cylates is productive of the corresponding 6-fluoro- 17a-alkyl-3,17;9dihydroxyandrostane 3,17-diacylates and 6-fluoro17m-alkyl-3,17fi-dihydroxy 19 norandrostane 3, l7-diacylates. When the 3,17diacy1ate is produced the ester groups at the 3-position and the 17-position are the same or different depending on the ester group present at the 17-position of the starting compound and the esterifying agent used to effect esterification at the 3 position. The 3-acylates of 6-fluoro-17a-alky1-3,17l3-dihydroxyandrostanes (and the 17-acylates thereof) and 6- fiuoro-17x-alkyl-3,l7fl-dihydroxy-19-norandrostanes (and the '17-acylates thereof) possess the same activities as the parent compounds. In addition, the 3-acylates characteristicallypossess greater oil solubility and a more extended duration of activity than their parent compounds.

Still other novel compounds of this invention are represented by the formula:

represents hydrogen, hydroxyl or keto. The term Acyl as used herein refers to an acyl radical of an organic carboxylic acid, preferably a hydrocarbon carboxylic acid, containing from one to twelve carbon atoms, inclusive.

The compounds of Formula IB possess useful therapeutic properties. They possess androgenic and anabolic activity and in addition exhibit antiestrogenic, antiosteoporotic, gonadotropin inhibiting and central nervous system regulating activity and are accordingly useful in the treatment of debilitated, osteoporotic, and hypogonadal conditions.

Administration of the steroids of Formula IB can be in conventional dosageforms, such as pills, tablets, cap sules, syrups or elixirs for oral use, or in liquid forms which are adaptable to the natural and synthetic steroid hormones for injectable products.

The novel steroids of Formula IB can be prepared according to the following reaction sequence:

wherein R, R and Z have the same meaning as previously given.

The starting steroids for the preparation of the compounds of Formula IB are, for example, 6-fluoro-17phydroxy-4-androsten-3-ones, 6-fluoro-17/3-hydroxy-l9-nor- 4-androsten-3-ones, 6-fluoro-l7B-hydroxy 4-androstene-3, ll-diones, 6-fluoro-17B-hydroxy-19-nor-4-androstene-3,1ldiones, 6-fluoro-1lfl,17B-dihydroxy-4-androsten-3-0nes, 6- fluoro-11B,17/3 dihydroxy-19-nor-4-androsten-3-ones, the 17-acylates thereof, 6-i'luoro-4-androstene-3,17-diones, 6- fiuoro-19-nor-4-androstene-3,17-diones, 6-fluoro-4-androstene-3,l1,17-triones, 6 fluoro-l9-nor-4-androstene-3,11, 17-triones, 6-fluoro-1 lB-hydroxy-4-androstene-3,17diones, and 6-fluoro-llfi-hydroxy-19-nor 4 androstene-Ehl'l-diones, disclosed in copending application Serial No. 716,- 026, filed February 19, 1958, now US. Patent 2,838,492, granted June 10, 1958.

The process for the preparation of the compounds of Formula IB comprises catalytically hydrogenating compounds of the type represented by Formula IIB, for example, 6-fiuoro-17/3-hydroxy-4-androsten-3-ones, 6-fiuoro- 17,8-hydroxy-19-nor-4-androsten-3 ones, 6 fluoro 17B (0 hydroxy-4-androstene-3,1l-diones, 6 fluoro-17/3-hydroxy- 6-fluor-o-l9-nor-4-androstene 3,11,17 triones, 6-fiuoro- 1 1fi-hydroxyl-androstene-B,17-diones, and 6-iluoro-l 1phydroxy-l9-nor-4-androstene-3,l7-diones, to obtain the compounds of Formula 1118, for'example, 6-fluoro-17/3 hydroxyan'drostan-B-0nes, 6 fiuoro l7fl-hydroxy-l9-nor androstan-3-ones, 6-flu0ro 17/3 hydroxyandr-ostane-3,1ldiones, 6-fluoro 17B hydroxy-l9-norandrostane-3,l l-diones, 6 -fiuoro 115,175 dihydroxyandrostan -3 ones, 6 fluoro 11,8,175-dihydroxy-19-norandrostan-3-ones, the 17 acylates thereof, 6 fluoroandrostane 3,17 diones, 6-fiuoro-19-norandrostane-3,l7-diones, 6-fluoroandrostane- 3,11,17-trines, 6-fluoro-19-norandrostane-3,11,17-triones, 6-fluoro-llfl-hydroxyandrostane-Ia,17-diones, and 6-fiuoro- 1lfi-hydroxy-l9-no-randrostane-3,17.- diones, respectively.

The catalytic hydrogenation of the compounds of Formula IIB to produce the compounds of Formula IIIB is accomplished by treating the compounds of Formula IIB with hydrogen in the presence of a noble metal catalyst, for example, palladium, rhodium, and the like, preferably palladium. The noble metal catalyst can be supported on a carrier, for example, charcoal, alumina, zeolite, zinc oxide, and the like. The reaction can be carried out at pressures of from atmospheric pressure to 100 pounds per square inch gauge, preferably at pressures between five and fifteen pounds per square inch gauge. The hydrogenation reaction is preferably carried out in the presence of a solvent, such as an organic solvent, for example, isopropyl alcohol, 95 percent ethyl alcohol, tertiary butyl alcohol, acetone, methyl ethyl ketone, dioxane, ethyl acetate and the like, or an alcohol, for example, ethyl alcohol, containing ten percent by volume of a 5 N solution of an aqueous acid, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, and the like.

The thus obtained compounds of Formula 1118 are then subjected to a reduction reaction, using one to 1.5 equivalents of sodium or potassium borohydride (although somewhat lesser or greater amounts of the borohydride are operative), to convert them to the compounds of Formula IVB, for example, 6-fluoro-3,17fl-dihydroxyandrostanes, 6-fiuoro-3,17;8 dihydroxy l9 norandrostanes, 6-fluoro- 3,17B-dihydroxy-androstan 11 ones, 6 fiuoro-3,17fl-dihydroxy-19-norandrostan-1l-ones, 6-fluoro 3,1 1/3,17B-trihydroxyandrostanes, 6-fiuoro 3,11,43,17/3 trihydroxy-l9- norandrostanes, the 17-acylates thereof, 6-fiuoro 3-hydroxyandrostan-17-ones, 6-fluoro-3-hydroxy-l9-norandrostan-17-ones, 6-fiuoro-S-hydroxyandrostane-11,17-diones, 6-fiuoro-3-hydroxy-19-norandrostane-11,17 diones, 6-fluor'o-3,11fidihydroxyandrostan l7 ones, and 6 fluoro- 3,11;8-dihydro xy l9-norandrostan 7 l7-ones, respectively. The reduction of the compounds of Formula IIIB is carried out in the presence of an organic solvent, for example, methanol, ethanol, isopropanol, pyridine, dimethylaniline, and the like, at a temperature of between minus ten and plus ten degrees centigrade, although somewhat higher or lower temperatures are operative. Preferably, the reduction reaction is carried out in the presence of a small amount of alkali.

6 fluoro 3,l7fidihydroxyandrostanes, 6 fluoro-3,17B- dihydroxy-l9-norandrostanes, 6-fluoro 3,17fl-dihydroxyand-rostan-l l ones, 6-fiuoro-3,17/3-dihydroxy-l9-norandrostan-l1ones, 6-fluoro 3,116,175 trihydroxyandrostanes, 6-fluoro-3,l1B,17,8-trihydroxy-19-norandrostanes, 6 -fluoro- 3-hydroxy androst an l7 ones, 6-fiuoro-3-hydroxy -l9- norandrostan-17 ones, 6-fiuoro 3 hydroxyandrostane- 1 1,17-diones, 6-fiuoro-3-hydroxy-19-norandrostane-11,17- diones, 6-fluoro-3,11,B-dihydroxyandrostan-17-ones, and 6-fluoro-3,1lfi-dihydroxy-l9-norandrostan-17-ones can be converted to their corresponding 3-acylates according to procedures well known in the art for the 3-acylation of dehydroepiandrosterone and 17a-methyl-5-androstene-3B, l7fi-diol. The 3-acylation of 6-fiuoro-3,l7 8-dihydroxyandrostane 17-acylates, 6-fluoro-3,l7fi-dihydroxy-l9-norandrostane 17-acylates, 6-tluoro 3,17/3 dihydroxyandrostan-ll-one 17-acelates, 6-fluoro-3,l7fi-dihydroxy-l9-norandrost-an-ll-one 17-acylates, 6-fluoro-3,11fi,17fl-trihydroxyandrostane 17 -acylates and 6-fluoro-3,l1fl,17 3-trihydroxy-l9-norandrostane l7-acylates is productive of their corresponding 3,17-diacylates. When the 3,17-diacylate is produced the ester groups at the 3-position and the l7-position are the same or different depending on the ester group present at the l7-position of the starting steroid and the esterifying agent used to effect esterification at the 3-position. The 3-acylates of the parent compounds (the compounds of Formula IVB) possess the same activities as the parent compounds. In addition, the 3-'1cylates characteristically possess greater oil solubility and a more extended duration of activity than their parent compounds.

The foregoing compounds of Formulae IA, IIA, IIIA, and IVA (Formula IA being a composite of Formulae IIIA and IVA) and IB, IIB, IIIB and IVB (Formula 113 being a composite of Formulae H13 and IVB) are all characterized by the presence of a 6-fluoro substituent. It should be noted that the configuration of the fluorine at the 6-position can be either 6a or 6B. Thus, substituting a 6fl-fluoro steroid as the starting material and following the procedures hereinbefore described and as exemplified below, there is produced as the final product of each example the corresponding fi-epimer. Where 6,6-epimer or a mixture predominating therein is employed as the starting material, any subsequent reaction product can be isolated either as 6fi-epimer or the aforesaid mixture of 60:- or 6B-epimers.

The following examples are illustrative of the process and products of the present invention, but are not to be construed as limiting. v

In the examples which follow, the Roman numeral following the name of a compound is used to indicate the relation of the compound to the reaction schemes depicted and described above.

EXAMPLE 1 A mixture containing 5.8 grams of Got-fltlOl'O-17amethyl-17,8-hydroxy-4-androsten-3-one, 270 milliliters of isopropyl alcohol and 3.5 gramsof five percent palladium on charcoal is hydrogenated at fifteen pounds per square inch gauge. The reaction mixture thus obtained is filtered and concentrated to dryness, leaving a residue. The residue is taken up in seventy milliliters of methylene chloride and chromatographed over 200 grams of Florisil (synthetic magnesium silicate). Thechromatographic column is eluted with 230-milliliter fractions as follows:

Fractions:

1-24 Ether: Skellysolve B hexanes::l:4. 2552 Ether: Skellysolve B hexanes:,:1:3.

Fractions 26-52 are combined and the solvent is evaporated therefrom to give 1.25 grams of a crude residue Which is recrystallized from an ether-Skellysolve B hexanes mixture to give 0.77 gram of 6a-fiuoro-l7ot-methyl-l7 3 hydroxy-Sfi-androstan-Ii-one (IIIA) melting at to 151' degrees centigrade and having an [ec] of minus nine degrees in ethanol and the following analysis:

AnaL-Calculated for C H FO C, 74.49; H, 9.69; F,

5.89. Found: C, 74.39; H, 9.70; F, 5.34.

6a-fluoro-l7a-methyl 17/3 hydroxy-5ot-androstan-3-one (IIIA), melting at -9" C., is present in the crystallization mother liquors and can be isolated by additional chromatography followed by crystallization from ether- Skellysolve B hexanes mixture.

Alternatively, the two isomers can be separated by reaction of the crude residue mixture from the hydrogenation with three milliliters of pyrrolidine in 25 milliliters of methanol at reflux temperature and under an atmosphere of nitrogen for about two minutes. The 3-pyrrolidyl enamines of the 5m and 5/3 compounds thus formed are then separated by crystallization. The first crop of crys- 27 tals of the 3-pyrrolidyl enamine which forms is removed, and is dissolved by adding thereto 200 milliliters of methanol containing ten milliliters of ten percent sodium hydroxide solution and warming under a nitrogen atmosphere' at approximately fifty degrees centigrade for about twenty minutes. The mother liquor, containing the remaining 3-pyrroidy1 enarnine, which is left following removal of the first crop of crystals, has added thereto 175 milliliters of methanol containing ten milliliters of ten percent sodium hydroxide solution followed by warming at approximately fifty degrees eentigrade under a nitrogen atmosphere for about twenty minutes. The solutions are then cooled, neutralized with acetic acid and concentrated to near dryness under reduced pressure. The residues thus obtained are extracted with ether and the ether extract is washed, dried, and evaporated to dryness. Crystallizations from acetone-Skellysolve B hexanes give the pure a and 55 isomers, 6or-fluoro-17m-methyl-17/8- hydroxy-5a-androstan 3 one and 6a-fluoro-17a-methyl- 17B-hydroxy-5fi-androStan-3-one, respectively.

Similarly, substituting other 6a-fluoro-l7m-alkyl-17B- hydroxy-4-androsten-3-ones, for example, 60t-flllOIO-17OL- ethyl-17fl-hydroxy-4-androsten-3-one, for 60t-fiuO1'O-170tmethyl-17B-hydroxy-4-androsten-3-one is productive of other 6a-fiuoro-l7oc-alkyl-175-hydroxy 5/3 androstan-3- ones and 6oc-fill0l'0-17oL-alkyl-17B-llYdIOXY-SOL-31'ld105t8ll- 3-ones, for example, Ger-fluoro-17a-ethyl-l7B-hydroxy-5fiandrostan-3-one and fiot-fillOI'O-170t-Ctl'1Yl-17fi-hYdl'OXY-5OL- androstan-3-one.

Likewise, substituting 6a-fluoro 1704 methyl-17/3-hydroxy-4-androsten-3-one 17-acylates and other 6a-fluoro 17a-alkyl-l7;8-hydroxy-4-androsten-3-one 17-acylates for 6a-fluoro 17a-methy1-l7fi-hydroxy-4-androsten-3-one is productive of 6u-fluoro-17a-methyl-17,8-hydroxy-5fl-audrostan-3-one l7-acylates (and the Sa-epimers thereof), and other 6a-fluoro-17a-alkyl-17B-hydroxy-5fi-androstan- 3-one l7-acylates (and the 5ot-epimers thereof). Representative of the 17-acylates thus produced are the 17- acetate, 17-propionate, 17-butyrate, l7-valerate, 17-hexanoate, 17-1aurate, l7-trimethylacetate, 17-isobutyrate, l7- isovalerate, 17-cyclohexane-carboxylate, 17-benzoate, l7-

phenylacetate, 17-,8-phenylpropionate, 17-(o, m-, ptoluate), 17-hernisuccinate and 17-hemiadipate.

EXAMPLE 2 6 a-fluoro-J 7 a-methyl-3J 7 B-dihydroxy-S ,B-androstanes (IVA) A suspension of 0.2 gram of 6oc-fiu0rO-17oc-m6thYl-17B- hydroxy-Sfl-androstan-B-one in ten milliliters of 95 percent ethyl alcohol is stirred with a solution of 100 milli grams of sodium borohydride in two milliliters of onetenth normal aqueous sodium hydroxide solution. After stirring for ten minutes the mixture is diluted with water and dilute aqueous acetic acid is added until a pH of six is reached. The product which precipitates is removed by filtration, washed with water, and dried in vacuo to give 6a-fluoro-17a-methyl-3a,l7B-dihydroxy 5fi-androstane, a crystalline solid. 6a-fluoro-17a-methyl-3fi,175-d} hydroxy-5,8-androstane is present in the mother liquor and is isolated by chromatography and further crystallization.

Similarly, the 17-acylates of 6a-fiuoro-17a-methyl-17B- hydroxy-SB-androstau-Ii-one, and other 6oc-fiL101'0l7aalkyl 176 hydroxy-5/i-androstan-3-ones and the 17- acylates thereof, can be substituted for 6a-fiuoro-17amethyl-17B-hydroxy-SB-androstan-3-one to obtain the 17- acylates of 6a-fluoro-17u-methyl-3oc,17fi-dihydroxy-5flandrostane (and the 3fl-epimers thereof), and other 6afluoro 170: alkyl-17B-hydroxy-3a,17[3-dihydroxy-5fiandrostanes and the 17-acylates thereof (and the 3,3-epimers thereof).

, EXAMPLE 3 6 oc-flLlOrO-I 7zx-m ethyl-3 ,1 7,8-dihydroxyJar-androstanes (IVA) A suspension of 0.2 gram of 6oc-fluoro-17ot-methyl-17fl- :hydroxy-5 z androstan-3-one in ten milliliters of per cent ethyl alcohol is stirred with a solution of milligrams of sodium borohydride in two milliliters of onetenth normal aqueous sodium hydroxide solution. After stirring for ten minutes the mixture is diluted with water and dilute aqueous acetic acid is added until a pH of six is reached. The product which precipitates is removed by filtration, washed with water, and dried in vacuo to give 6a-luoro 17a methyl-3B,17fi-dihydroxy-5a-androstane, a crystalline solid. 6a-fiuoro-l7a-methyl-3u,175-dihydroxy-5a-androstane is present in the mother liquors and is isolated by chromatography and further crystalliza tron.

Similarly, the 17-acylates of 6lX-fillOI'O-170t-l'll6tl'lYl-5ctandrostan-3-one, and other Got-fluoro-17ot-alkyl-5a-androstan-3-ones and the 17-acylates thereof can be substituted for 6a-fluoro-Nor-methyl-l7,8-hydroxy-5ot-androstan-3-one dihydroxy-5u-androstane (and the 3a-epimers thereof), and other 60t-fil101'O-l70t-3lkYl-3B,17j3-(llhYdIOXY-50t-fllldl'0- stanes and the l7-acylates thereof (and the 3a-epimers thereof).

EXAMPLE 4 Substituting 6a-fluoro-17a-methyl-17B-hydroxy-l9-nor- 4-androsten-3-one for 6a-fiuoro-l7tx-methyl-l7fl-hydroxy- 4-androsten.3-one and following the procedure of Example l is productive of 6a-fiuor0-17a-methyl-17B-hydroxyl9-nor-5fi-androstan-3-one and 6ot-fiuoro-17a-methyl-17B- hydroxy-19-nor-5'a-androstan-3-one. 7 Similarly, substituting other 6a-fluoro-l7a-alkyl-l7flhydroxy-19-nor-4-androsten-3-ones, for example, 6u-fluoro-l7a-ethyl-17B-hydroxy-l9-nor-4-androsten-3-one, for 6a-fluoro-17u-methyl-17fi-hydroxy-4androsten-3-one and following the procedure of Example 1 is productive of other 6ot-fluoro-l7a-alkyl-17fi-hydroxy-19-nor-5B-androstan-3-ones and 6a-fiu'oro-17u-alkyl-l7fi-hydroxy-19- nor-5a-androstan-3-ones, for example, 6oc-fil10I0-17zx-EUJY1- 17/3-hydroxy-l9-nor-5B-androstan-3-one and 6a-fluorol7a-ethyl-17fl-hydroxy-19-nor-5o -androstan-3-one.

Likewise, substituting 6ct-fluoro-l7or-rnethyl-17,3hydroxy-19-nor-4-androsten-3-one 17-acylates and other 6afiuoro 17a alkyl 17p hydroxy 19 nor 4 androsten 3-one 17-acylates in the procedure of Example 1 is productive of 6ot-fluoro-17a-methyl-l7fi-hydroxy-19-nor- 5a-androstan-3-one l7-acylates. thereof, and other 6a-fiuoro-17a-alky1-17B-hydroxy-19- nor-5'a'androstan-3-one 17-acylates (and the Sfl-epimers thereof.) Representative of the 17-acylates thus produced are those named above in Example 1.

EXAMPLE 5 v Substituting 6a-fluoro-l7a-methyl-l7j3-hydroxy-19-nor- 5B-androstan-3-one for Got-fiLlOIO-l7ot-I116tllYl-l7B-hYd1OXY- 5B-androstan-3-one and following the procedure of Example 2. is productive of 6a-fluoro-17wmethyl-3a,17B- dihydroxy-19-nor-5B-androstane and 6OL-flUOI'O-17t1-methyl-3B,l7fi-dihydroxy-19-nor-5fl-androstane.

Similarly, the substitution of the 17-acylates of 6a fluoro 17a methyl 17B hydroxy 19 nor Sfl-androstan-B-one and other 6 x-fluoro-17a-alkyl-17/i-hydroxyl9-nor-55-androstan-3-ones and the l7-acylates thereof for 6u-fluoro-17a-rnethyl-l7,8-hydroxy-Sfi-androstan-B-one in the procedure of Example 2 is productive of the 17- acylates of 6zx-fluoro-17u-methyl-3a,17B-dihydroxy-l9-nor- SB-androstane (and the 3,6-epirners thereof), and other 6a iiuoro 17a alkyl 30,17/3 dih'ydroxy l9 nor Sfi-androstanes and the 17-acylates thereof (and the 3;?- epimers thereof (and the Sfi-epirners EXAMPLE 6 6a-fluor0-17a-methyl-3J 7,8-dihydrxy-19-nora-androstrmes (IVA) Substituting 6a-fiuoro-17tx-methyl-l7fi-hydroxy19-nor- 5 u-androstan-3-one for 6a-lluoro-17a-methyl-17 8-hydroxy- 5e-androstan-3-one and following the procedure of EX- ample 3 is productive of 6u-fluoro-17a-methyl-3fl,17B- dihydroxy-19-nor-5ot-androstane and 6a-fluoro-l7a-methyl-3a,17fi-dihydroxy-19-nor-5'a-androstane.

Similarly, the substitution of the l7-acylates of 6afiuoro 17c: methyl 17;? hydroxy 19 nor 5a androstan-3-one and other 6a-fiuoro-17a-alkyl-17B-hydroxy- 19-nor-5u-androstan-3-ones and the 17-acylates thereof for 6u-fluoro-17a-methyl-17B-hydroxy-5a-androstan-3-one in the procedure'of Example 1 is productive of the 17- acylates of 6a-fluoro-l7a-methyl-3B,17fi-dihydroxy-l9-nor- 5a-androstane (and the 3e-epimers thereof), and other 60: fluoro 17a alkyl 35,175 dihydroxy 19 nor Sa-androstanes and the 17-acylates thereof (and the 30:- epimers thereof).

EXAMPLE 7 The 6 3-flu0ro epimers A. Substituting tip-fluoro-Hot-methyl-17(3-hydroxy-4- androsten-3-one (and the corresponding 19-nor compound) and 6rx-fiuoro-17a-methyl-17fi-hydroXy-4-androsten-3-one and following the procedure of Example 1, there is produced 6e-fluoro-17a-methyl-17fi-hydroxy-5fiandrostan-3-one (and the corresponding 19-nor compounds) and 6fl-fiuoro-Nix-methyl-17fl-hydroxy-5wandrostan-S-one (and the corresponding 19-nor compound).

In like manner, the l7-acylates of 6fi-fiuoro-17a-methyl- 17fl-hydroxy-4-androsten-3-one (and the corresponding l9-nor compounds) are converted to 6/3-fiuoro-17mmethyl-17fl-hydroxy-5fi-androstan-3-one 17-acylates (and the corresponding 19-nor compounds), and 6;8-fiuoro-17 xmethyl-l7fl-hydroxy-5a-androStan-B-one 17-acylates (and the corresponding 19-nor compounds).

' androstan-3-one (and the corresponding l9-nor compound) for 6a-fiuoro-17ct methyl-17B-hydroxy-5B androstan-3-one and followingthe procedure of Example 2 there is produced 66-fluroro-17a-methyl-3a,17fl-dihydroxy-SB-androstane (and the corresponding 19-nor compound) and 6fi-fiUOIO-17oc-m6thYI-3fi,17fi-dihYti1'OXy-5flandrostane (and the corresponding 19-nor compound).

In like manner, the 17-acylates of 65-fluoro-17a-methyll7B-hydroxy-5fi-androstan-3-0ne (and the corresponding l9-nor compounds) are converted to 6B-flUOIO-l7zx-m6thyl 17;? hydroxy 3a,17fl dihydroxy 513 androstane l7-acylates (and the corresponding 19-nor compounds) and 66-fiuoro-17a-methyl-3B,17fi-dihydroxy-5B-androstane l7-acylates (and the corresponding 19-nor compounds).

C. Substituting 6fi-fluoro-l7a-methyl-175-hydroxy-5aandrostan-3-one (and the corresponding 19-nor compound) for 6a-fiuoro-l7a-methyI-Sa-androstan 3-one and following the procedure of Example 3 there is produced 6fl-fluoro-17a-methyl-3B,17,3-dihydroxy-5wandrostane (and the corresponding 19-nor compound), and 6,6- fluoro-17tx-methvl-3e.17B-dihydroxy-Srx-androstane (and the corresponding 19-nor compound).

In like manner, the 17-acylates of 6,8-fluoro-17a-me-thvl- 17fi-hydroxy-5a-androstan-3-one (and the corresponding l9-nor compounds) are converted to 6fi-fluoro-17a-methyl- 3p,17B-dihydroXy-5a-androstane 17-acylates (and the corresponding 19-nor compounds), and 6B-fluoro-17a-methyl- 3u,17B dihydroxy 5a androstane 17-acylates (and the corresponding l9-nor compounds).

EXAMPLE 8 oa-fluoro-l 75-h dr0xyandr0stan-3-0nes (IIIB) A mixture containing five grams of 6a-fluoro-17B-hydroxy-4-androsten-3-one. 250 milliliters of isopropyl alcohol and 0.5 gram of five percent palladium on charcoal is hydrogenated at fifteen pounds persquare inch gauge. The reaction mixture thus obtained is filtered and concentrated to dryness, leaving a residue. The residue is taken up in twenty-five milliliters of methylene chloride and chromatographed over- 250 grams of Florisil (synthetic magnesium silicate). The chromatographic column is eluted with Skellysolve B hexanes containing increasing proportions of acetone. The eluates,

obtained in fractions from the chromatographic column,

are evaporated to dryness to give residues. The crystalline residues obtained from the fractions eluted with Skellysolve B hexanes containing five to eight percent acetone are combined and recrystallized from ether-SkellysolveB hexanes to give 6a-fluoro-17B-hydroXy-5a-androstan-3-one, a crystalline solid having a melting point of 161-163" C. 6oi-fluoro-17fi-hydroXy-5/3-androstan-3-one is present in the mother liquors and is obtained by further fractional crystallization.

Alternatively, the two isomers can be separated by reaction of the crude residue mixture from the hydrogenation with three milliliters of pyrrolidine in 25 milliliters of methanol at reflux temperature and under an atmosphere of nitrogen forabout two minutes. The 3-pyrrolidyl enamines of the 50: and 55 compounds thus formed are then separated by crystallization. The first crop of crystals of the 3-pyrrolidyl enamine which forms is removed, and is dissolved by, adding thereto 200 milliliters of methanol containing ten milliliters of ten percent sodium hydroxide solution and warming under a nitrogen atmosphere at approximately fifty degrees centigrade for about twenty minutes. The mother liquor, containing the remaining 3-pyrrolidyl enamine, which is left following removal of the first crop of crystals, has added thereto 175 milliliters of methanol containing ten milliliters of ten percent sodium hydroxide solution followed by warming at approximately fifty degrees centigrade under a nitrogen atmosphere for about twenty minutes. The solutions are then cooled, neutralized with acetic acid and concentrated to near dryness under reduced pressure. The residues thus obtained are extracted with ether and the ether extract is washed, dried, and evaporated to dryness. Crystalliza-tions from acetone-Skellysolve B hexanes give the pure 50 and 5B isomers, 6a-fluoro-l7fi-hydroXy-Sa-androstan-3-one and 6a-fluoro-17fi-hydroXy-5pandrostan-S-one, respectively.

Similarly, substituting 6u-fluoro-l7B-hydroXy-4-androsten-3-one 17-acylates for 6a-fluoro-17B-hydroXy-4-androsten-3-one is productive of 6a-fiuoro-17/3-hydroXy-Sa-androstan-3-one 17-acylates (and the Sp-epimersthereof). Representative of the 17-acylates thus produced are the 17-acetate, 17-propionate, 17-butyrate, 17-valerate, l7- hexanoate, 17-laurate, 17-trimethylacetate, 17-isobutyrate, 17-isovalerate, 17-cycloheXane-carboxylate, 1'7-benzoate, 17-phenylacetate, 17-(fl-phenylpropionate), l7-(o-, m, p-toluate), 17-hemisuccinate, and 17-hemiadipate.

EXAMPLE 9 6 oc-fl uoro- {I 75-11 ihyd roxy-S ot-androstones I VB) To a solution of one gram of 6a-fluoro-l7 8-hydroxy- Swandrostan-3-one in fifty milliliters of methanol, chilled to about five degrees centigrade, there is added a solution of 57 milligrams. of potassium borohydride in one milliliter of water (containing one drop of five percent sodium hydroxide solution) with rapid stirring. Stirring is continued for about fifteen to thirty minutes after which the mixture is quenched with fifty milliliters of water containing 0.5 milliliter of acetic acid. The solution is then concentrated under reduced pressure to give a mixture of 6a-fiuoro-3,8,17fi-dihydroxy-5tx-androstane and 6a-fiuoro- 3a,17,8-dihydroXy-5a-androstane together with a small amount of unchanged starting material. The crude product is then dissolved in methylene chloride and chromatographed over grams of Florisil (synthetic magnesium silicate). The chromatographic column is eluted with Skellysolve B hexanes containingincreasing proportions of acetone to give, after removal of the eluant, 6a-fiuoro- 36,17B-dihydroxy-a-androstane, a crystalline solid, and

6wfluoro-3cx,HIS-dihydroxy 5a androstane, a crystalline solid, both of which can be further purified by recrystallization from acetone-hexane mixture.

Similarly substituting 6a-fiuoro-l7B-hydroxy-5ot-androstan-3-one 17-acylates for 6u-fiuoro-l7 3-hydroxy-5a-androstan-3-one is productive of 6a-fluoro-3fi,l7 3-dihydroxy-5a-androstane 17-acylates and 6a-fiuoro-3cx,l7/3-dihydroxy-S'a-androstane l7-acylates.

In like manner substituting 6a-fluoro-17 3-hydroxy-5flandrostan-3-one (and the l7-acylates thereof) for 60- fluoro-17fi hydroxy-5a-androstan-3-one is productive of 6a-fiuor-o-3a,175-dihydroxy-5fl-androstane (and the 17- acylates thereof) and 6a-fluoro-3fi,l7fl dihydroxy-5 8-androstane (and the l7-acylates thereof).

EXAMPLE 10 6a-fln0r0-17fl-hydr0xyandrostane-3,1I-diorzes (IIIB) A mixture containing one gram of 6a-fiuoro-17B-hydrox-y-4-androstene-3,ll-dione, fifty milliliters of isopropyl alcohol and 200 milligrams of five percent palladium on charcoal is hydrogenated at fifteen pounds per square inch gauge. The reaction mixture thus obtained is filtered and concentrated to dryness, leaving a residue. The residue is taken up in twenty milliliters of methylene chloride and chromatographed over fifty grams of Florisil (synthetic magnesium silicate). The chromatographic column is eluted with Skellysolve B hexanes containing increasing proportions of acetone to give, after removal of the eluant, 6m-fiuoro-l7,8-hydroxy-5fi-androstane-3,1ldione, a crystalline solid, and 6a-fluor0-l7,8-hydroxy-5ocandrostane-3,ll-dione, a crystalline solid, both of which can be further purified by recrystallization from acetonehexane mixture.

Alternatively, the 50cand Sfl-epimers are separated by following the pyrrolidyl enamine procedure disclosed in Example 8.

Similarly substituting 6a-fluoro-17fl-hydroxy-4-androstene-3,l1-dione 17-acylates for 6a-fluoro-17B-hydroxy-4- androstene-3,11-dione is productive of 6a-fiuoro-l7fi-hy droxy-5ot-androstane-3,ll-dione l7-acylates (and the 5,3- epimers'thereof). Representative of the 17-acylates thus produced are those named in Example 8.

To a solution of one gram of 6a-fluoro-l7fl-h3'droxy- 5a-androstane-3,1I-dione in fifty milliliters of methanol, chilled to about five degrees centigrade, there is added a solution of 57 milligrams of potassium borohydride in one milliliter of water (containing one drop of five percent sodium hydroxide solution) with rapid stirring. Stirring is continued for about fifteen to thirty minutes after which the rniXture is quenched With fifty milliliters of water containing 0.5 milliliter of acetic acid. The solution .is then concentrated under reduced pressure to give a mixture of 6or-fiuoro-3 3,l7B-dihydroxy-5u-androstan 11 one and 6a fluoro 30;,17B dihydroxy 5ozandrostan-ll-one together with a small amount of unchanged starting material. The crude product is then dissolved in methylene chloride and chromatographed over 100 grams of Florisil (synthetic magnesium silicate). The chromatographic column is eluted with Skellysolve B hexanes'containing increasing proportions of acetone togive, after removal of the eluant, 6a-fiuoro- 35,175 dihydroxy 50c androstan l1 one, a crystalline solid, and 6a-fluoro-3a,17fi-dihydroxy-5a-androstanll-one, a crystalline solid, both of which can be further purified by recrystallization from acetone-hexane mixture.

Similarly, substituting 60c fluoro 17,8 hydroxy- 50c androstane 3,11 dione l7 acylates for 60- fiuoro 17 3 hydroxy 5oz androstane 3,11 dione is productive of; 6a fluoro 3a,17fl dihydroxy 50c- EXAMPLE l2 6a-flu0r0-I1BJ7fi-dihydroxyandr0stan-3-ones (IIIB) A mixture containing five grams of 6a-fiuoro-llfi.l7fidihydroxy-4-androsten-4-one, 250 milliliters of isopropyl alcohol and one gram of five precent palladium on charcoal is hydrogenated at fiften pounds per square inch gauge. The reaction mixture thus obtained isfi tered and concentrated to dryness, leaving a residue. The residue is taken up in 25 milliliters of methylene chloride and chromatographed over 250 grams of Florisil (synthetic magnesium silicate). The chromatographic column is eluated with Skellysolve B hexanes containing increasing proportions of acetone to give, after removal of the eluant, 6a-fiuoro-l1B,l7B-dihydroxy-SB-androstan- 3-one a crystalline solid, and 6a-fiuoro-11fl17fi-dihydroxy-Sa-androstan-3-one, a crystalline solid, both of which can be further purified by recrystallization from acetone-hexane mixture.

Alternatively, the 5ocand S/R-epimers are separated by following the pyrrolidyl enarnine procedure disclosed in Example 8.

Similarly substituting 6a-fiuoro-1 1 6,17r3-dihydroxy-4- androsten-3-one 17-acylates for 6a-fluoro-l1fil7B-dihydroxy-4-androsten-3-one is productive of 6u-fiuoro-l15, 175 dihydroxy 5a androstan 3 one 17 acylates (and the Sfli-epimers thereof). Representative of the 17- acylates thus produced are those named in Example 8.

EXAMPLE 13 To a solution of one gram of 6a-fiuoro-1lfl17B-dihydroxy-5a-androstan-3-one in fiftymilliliters of methanol, chilled to about five degrees centigrade, there is added a solution of 57 milligrams of potassium borohydride in one milliliter of water (containing one drop of five percent sodium hydroxide solution) with rapid stirring. Stirring is continued for about fifteen to thirty minutes after which the mixture is quenched with fifty milliliters of water containing 0.5 milliliter of acetic acid. The solution is then concentrated under reduced pressure to give a mixture of 6oz-fluoro-3fl,l15,17/3-trihydroxy-5a-androstane and 6a-fiuoro-3a,l1 8,17B-trihydroxy-5a-androstane, together with a small. amount of unchanged starting material. The crude product is then dissolved in methylene chloride and chromatographed over grams of Florisil (synthetic magnesium silicate). The ch omatographic column is eluated with Skellysolve B hexanes containing increasing proportions of acetone to give, after removal of the eluant, 6a-fluoro-3B,l1,6,l7fi-trihydroxy- 5u-androstane, a crystalline solid, and 6ofitlOr0-3a,l1}3, 17fl-trihydroxy-5ot-androstane, a crystalline solid, both of which can be further purified by recrystallization from acetone-hexane mixture.

Similarly, substituting 6m-fiuoro-l1B,l75-dihydroxy-5uandrostan-3-one 17-acylates for 6u-fluoro-llfi,l7fl-dihydroxy-5a-androstan-3-one is productive of 6a-fiuoro-3fi, 1lo,l7fl-trihydroxy-ia-androstane l7-acylates and 60afluoro-30H1B,l7B-trihydroxy-5a-androstane l7-acylates.

In like manner, substituting 6a-fluoro-llfi3,l7 8-dihydroxy-5fi-androstan-3-one (and the 17-acylates thereof) for 60 fluoro 115,175 dihydroxy 50c androstan 3- one is productive of 6or-fiuoro-3a,l15,17/3-trihydroxy-5fiandrostane (and the 17-acy1ates thereof) and 6a-fluoro- 3[i,1l6,l7fi-trihydroxy-Sfl-androstane (and the 17-acylates thereof).

EXAMPLE 14 6a-fluoroandrostane-3J7-di0nes (111B) A mixture containing'two grams of 6a-fluoro-4-androstene-3,l7-dione, 100 milliliters of isopropyl alcohol and 0.4 gram of five percent palladium on charcoal is hydrogenated at fifteen pounds per square inch gauge. The reaction mixture thus obtained is filtered and concentrated to dryness, leaving a residue. The residue is taken up in fifteen mililliters of methylene chloride and chromatographed over 100 gramsof Florisil (synthetic magnesium silicate). The chromatographic column is eluated with Skellysolve B hexanes containing increasing proportions of acetone to give, after removal of the eluant, 6a-fiuoro-5B-androstane-3,l7-dione, a crystalline solid, and 6 -fiuoro-a-androstane-3,17-dione, a crystalline solid, both of which can be further purified by recrystallization from acetone-hexane mixture.

Alternatively, the 5aand S/E-epimers are separrted by following the pyrrolidyl enamine procedure disclosed in Example 8.

EXAMPLE 15 6 u-fluoro-3-hydroxy-5 a-androstzm-l 7-0nes I VB To a solution of one gram of 6a-fluoro-Sa-androstane- 3,17-dione in fifty milliliters of methanol, chilled to about five degrees centigrade, there is added a solution of 57 milligrams of potassium borohydride in one milliliter of water (containing one drop of five percent sodium hydroxide solution) with rapid stirring. Stirring is continued for about fifteen to thirty minutes after which the mixture is quenched with fifty milliliters of water containing 0.5 milliliter of acetic acid. The solution is then concentrated under reduced pressure to give a mixture of 6a-fluoro-3 3-hydroxy-5a-androstan-17-one and 6a-fluoro- 3oc-hYClIOXY-5a-fltldl05tall-17-0116, together with a small amount of unchanged starting material. The crude prodnot is then dissolved in methylene chloride and chromatographed over 100 grams of Florisil (synthetic magnesium silicate). The chromatographic column is eluted with Skellysolve B hexanes containing increasing proportions of acetone to give, after removal of the eluant, a-fiuoro- 3fl-hydroxy-5a-androstan-17-one, a crystalline solid, and Got-fillOYO-3cc hydroxy-Sa-androstan-l7-one, a crystalline solid, both of which can be further purified by recrystallization from acetone-hexane mixture.

In like manner, substituting 6a-fiuoro-5B-androstane- 3,17-dione for 6a-fluoro-5a-androstane-3,l7-dione is productive of 6a-fiuoro-3u-hydrQXy-Sfi-andmsfan-l7-one and 6oz-fil1OIO-3 B-hydroxy-S B-androstanl 7-one.

EXAMPLE l6 6a-flu0roandrostane-3J1,17-trione (IIIB) A mixture containing five grams of 6a-fiuoro-4-androstene-3,ll,l7-trione, 250 milliliters of isopropyl alcohol and one gram of five percent palladium on charcoal is hydrogenated at fifteen pounds per square inch gauge. The reaction mixture thus obtained is filtered and concentrated to dryness, leaving a residue. The residue is taken up in forty milliliters of methylene chloride and chro-matographed over 200 grams of Florisil (synthetic magnesium silicate). The chromatographed' column is eluted with Skellysolve B hexanes containing increasing proportionsof acetone to give, after removal of the eluant, 6a-fiuoro-5 3-androstane-3,ll,l7-trione, a crystalline solid, and 6a-fiuoro-5a-androstane-3,l1,17-trione, a crystalline solid, both of which can be further purified by recrystallization from acetone-hexane mixture.

Alternatively, the 5aand SB-epimers are separated by following the pyrrolidyl enamine procedure disclosed in Example 8.

EXAMPLE 17 To a solution of one gram of 6a-fluoro-5a-androstane- 3,11,17-trione in fifty milliliters of methanol, chilled to about five degrees centigrade, there is added a solution of 57'milligrams of potassium borohydride is one milliliter of water (containing one drop of five percent sodium hydroxide solution) with rapid stirring. Stirring is continued for about fifteen to thirty minutes after which the mixture is quenched with fifty milliliters of Water containing 0.5 milliliter ofacetic acid. The solution is then concentrated under reduced pressure to give a mixture of 6a-fluoro-3B-hydroxy-5n androstane-ll,17-dione and Secfluoro 30c hydroxy-5a-androstane-1 1,17-dione, together with a small amount of unchanged starting material. The crude product is then dissolved in methylene chloride and chromatographed over 100 grams of Florisil (synthetic magnesium silicate). The chromatographic column is eluted with Skellysolve B hexanes containing increasing proportions of acetone to give, after removal of the eluant, 6a-fiuoro-3,8-hydroxy-5a-androstane-11,17-dione, a crystalline solid, and 6a-fiuoro-3u-hydroxy-5rx-androstane- 11,17-dione, a crystalline solid, both of which can be further purified by recrystallization from acetone-hexane mixture.

In like manner, substituting 6u-fluoro-5B-androstane- 3,1'1,l7-trione for 6on-fitl01'O-5ct-flf1dl05i3l'l8-3,11,17-i1'i0116 is productive of 6oc-fiuoro-3a-hydroxy-5wandrostane-l1, l7-dione and 6a-fiuoro-3l3-hydroxy-Sfi-androstane-l1,17- dione.

EXAMPLE 18 A mixture containing ten grams of Goa-flUOIO-Ilfl-hY- droxy-4-androstene-3,l7-dione, 500 milliliters of isopropyl alcohol and two grams of five percent palladium on charcoal is hydrogenated at fifteen pounds per square inch gauge. The reaction mixture thus obtained is filtered and concentrated to dryness, leaving a residue. The residue is taken up in fifty milliliters of methylene chloride and chromatographed over 300 grams of Florisil (synthetic magnesium silicate). The chromatographic column is eluted with Skellysolve B hexanes containing increasing proportions of acetone to give, after removal of the eluant, 6a-fiuoro-l1,B-hydroxy-Sfl-androstane-3,17-dione, a crystalline solid, and 6a-fluoro-1lB-hydrOXy-Sa-andmstane- 3,17-dione, a crystalline solid, both of which can be further purified by recrystallization from acetone-hexane mixture.

Alternatively, the Socand Sfi-epimers are separated by following the pyrrolidyl enamine procedure disclosed in Example 8.

EXAMPLE l9 6 a-flLlOr0-3,1 I fi-dihydroxy-Su-androstan-I 7 -ones (I VB) To a solution of one gram of 6a-fluoro-llfl-hydroxy-5aandrostane-3,l7-dione in fifty milliliters of methanol, chilled to about five degrees Centigrade, there is added a solution of 57 milligrams of potassium borohydride in one milliliter of Water (containing one drop of five percent sodium hydroxide solution) with rapid stirring. Stirring is continued for about fifteen to thirty minutes after which the mixture is quenched with fifty milliliters of Water containing 0.5 milliliter of acetic acid. The solution is then concentrated under reduced pressure to give a mixture of 6n-fiuoro-3,8,1lfi-dihydroxy-Su-androstan-l7-one and 60:- fluoro 30,l 1B dihydroxy5a-androstan-17-one, together with a small amount of unreacted starting material. The crude product is then dissolved in methylene chloride and chromato-graphed over grams of Florisil (synthetic magnesium silicate). The chromatographic column is eluted with Skellysolve B hexanes containing increasing proportions of acetone to give, after removal of the eluant, 6a-fiuoro-3B,llfi-dihydroxy-Su-androstan-3-one, a crystalline solid, and 6a-fluoro-3a,l1 8-dihydroxy-5a-androstan- 3-one, a crystalline solid, both of which can be further purified by recrystallization from acetone-hexane mixture.

in like manner, substituting 6ot-fluoro-1lB-hydroxy-5fl- 1 5 andrstane-3 17-dione for 6afiuoro-1 15-hydroxy-5ct-androstane-3 ,17-dione is productive of 6a-fiuoro-3 0;,15-dihydroxy-55-androstan-17-one and 6a-fiuoro-35,115dihydroxy-55-androstan-17-one.

EXAMPLE 20 The 60t-flllOTO-19-HOI steroids Substituting the corresponding 6u-fiUO1'0-19-110f starting steriods in each example and following the procedures of Example 8 through 19 there are obtained the corresponding 6(Z-fluOl'O-19-I101' end products of each example, e.g., 60c fluoro 175 hydroxy 19 nor 55 androstan- 3-one, 6u-fiuoro-175-hydroxy19-nor-5a-androstan-3-one, and'the 17-acylates thereof, (Example 8), 6e-fluoro-35, 175 dihydroxy 19 nor a androstane, 6oz fluoro- 30:,175 dihydroxy 19 nor 5a androstane, 6afiuoro 3u,175 dihydroxy 19 nor 55 androstane, 6m fluoro 35,175 dihydroxy 19 nor 55 androstane, and the 17-acylates thereof, (Example 9), 6a-fiuoro- 175 hydroxy l9 nor 55 androstane 3,11 dione, 6a fiuoro 175 hydroxy 19 nor 5a androstane- 3,11-dione, and the 17-acylates thereof (Example 10), 60L- fluoro 35,175 dihydroxy 19 nor 5oz androstan 11 one, 606 fiuoro 3u,175 dihydroxy 19 nor 5aandrostan 11 one, 60: fiuoro 30,175 dihydroxy 19- nor 55 androstan 11 one, 6a fluoro 35,175 dihydroxy 19 nor 55 androstan 11 one, and the 17-acylates thereof (Example 11), 6a-fluoro-115,175-dihydroxy 19 nor 50c androstan 3 one, 60c fluoro- 115,175 dihydroxy 19 nor 55 androstan 3 one, and the 17-acylates thereof (Example 12), Got-fluoro- 35,115,175 trihydroxy 19 nor 5a androstane, 60cfluoro 30:,115,17,8 trihydroxy 19 nor 5a androstane, 6a fluoro 3a,115,175 trihydroxy 19 nor 55- androstane, 6a fluoro 35,115,175 trihydroxy 19- nor-55-androstane, and the 17-acylates thereof, (Example 13), 6a fluoro 19 nor 5oz androstane 3,17 dione, 60s fiuoro 19 nor- 55 androstane 3,17 4 dione (Example 14), 6a fluoro 35 hydroxy 19 nor 50c androstan 17 one, 6a fluoro 3a hydroxy 19 nor- Sm androstan 17 one, 6a fiuoro 30c hydroxy- 19 nor 55 androstan 17 one, 600 fluoro 35 hydroxy 19 nor 55 androstan 17 one (Example 15), 60c fluoro 19 nor 50 androstane 3,11,.17 trione, 6a fluoro 19 nor 55 androstane 3,11,17 trione (Example 16), 60c fiuoro 35 hydroxy 19 nor 50candrostane 11,17 dione, 6x fiuoro 3e hydroxy 19- nor 5a androstane 11,17' dione, 60c fiuoro 30chydroxy 19 nor 55 androstane 11,17 dione, 60 fluoro 35 hydroxy 19 nor 55 androstane 11,17 dione (Exampe 17), 6oz fiuoro 115 hydroxy- 19 nor 5a androstane 3,17 dione, 60c fluoro 115- hydroxy 19 nor 55 androstane 3,17 dione (Example 18), 60c fluoro 35,115 dihyd'roxy 19 nor- 5a androstanl7 one, 6a iuoro 35,115 dihydroxy- 19 nor 5a androstan 17 one, 604 fiuoro 311,115- dihydroxy 19 nor 55 androstan 17 one, and 6afluoro 35,115 dihydroxy 19 nor 55 androstan- 17-one (Example 19).

EXAMPLE 21 The 65-flu0r0 epimers Substituting 65 fluoro 175 hydroxy 4 androsten- 3 -one for 60 fluoro 175 hydroxy 4 androsten 3- one and following the procedure of Example 8, there is produced 65 fiuoro 175 hydroxy 55 androstan 3- one and 65-fiuoro-175-hydroxy5x-androstan-3-one.

Likewise, substituting the corresponding 65-fiuoro and 65-fluoro-19-nor steroids for the starting compounds of Examples 9 through and following the procedures described therein, there are obtained the corresponding 65- fiuoro and 65-fiuoro-19-nor end products of each example.

This application is a continuation-in-part of application Serial No. 740,570, now abandoned, and application Serial No. 740,529, both filed June 9, 1958. Application Serial No. 740,570 is, in turn, a continuation-in-part of application Serial No. 699,502, filed November 29, 1957, now US. Patent 2,838,500, issued June 10, 1958. Application Serial No. 740,529 is, in turn, a continuation-in-part of application Serial No. 716,026, filed February 19, 1958, now US. Patent 2,838,492, issued June 10, 1958, which is, in turn, a continuation-in-part of application Serial No. 699,505, filed November 29, 1957, now abandoned.

It is to be understood that the invention is not to be limited to the exact details of operation or exact compounds shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art, and the invention is therefore to be limited only by the scope of the appended claims.

We claim: 1. A 6-fluo'ro compound of the formula:

F wherein R is selected from the group consisting of hydroxyl, OAcyl, and keto, the term Acyl representing the acyl radical of an organic carboxylic acid containing from one to twelve carbon atoms, inclusive, X is selected from the group consisting of the carbonyl radical and the hydroxymethylene radical, and Z is selected from the F wherein R is selected from the group 'consi s'tingo'f hydroxyl, OAcyl, and keto, the term Acyl representing the" acyl radical of an organic carboxyic acid containing from one to twelve carbon atoms, inclusive, X is selected'from" the group consisting of the carbonyl radical and the hydroxymethylene radical, and Z isselected front the group consisting of hydrogen, hydroxyl, and keto.

References Cited in the file'of' this patent UNITED STATES PATENTS 00 Campbell et a1. J une 1 0, 1-95 8 UNITED STATES PATENT OFFICE CERTIFICATION OF CORRECTION Patent No. 3,016,387 January 9 1962 John C. Balocock et a1.

certified that error appears in the above numbered pat- It is hereby and that the said Letters Patent should read as ent requiring correction corrected below.

Column 2 formula IVA should appear as lines 33 to 43 shown below instead of as in the patent:

formula 1B should appear as shown lines 59 to (2.9

the patent:

column 3, below instead of as in column 4, line 72 for "-ll[3,7B-" read 5 line 74, for "l7-acelates" read l7-acylates column 8 line 30 for "4androsten,3-0ne" read 4-androsten-3-one column 9, lines 27 and 28 for "compound) and" read com pound) for column 11, line '75 for "-3 l75-" read 45g l7- column 12 line 14L for "-4-androsten-4-one" read -4-androsten-3-one column l6 line 73 for "23539500" read 2.838500 Signed and sealed this 8th day of May 1962.,

(SEAL) Attest:

ERNEST W. SWIDER Attesting Officer DAVID L. LADD Commissioner of Patents 

1. A 6-FLUORO COMPOUND OF THE FORMULAR: 